The bioavailability of orally ingested drugs normally highly extracted by the liver is increased out of proportion to decreased hepatic clearance (HC) in patients with chronic liver disease. A similar increase in bioavailability would by expected for portal endogenous substances (PES) with great hepatic extraction normally entering the circulation via the portal vein and would markedly increase the area under the time-concentration curve (AUC). Methods of determining the systemic availability ratio (SAR) of PES have not been described. The hepatic extraction ratio of PES cannot be determined either since the portal vein and arterial concentrations are unequal. The rate of secretion or absorption, the SAR and HC of PES determine the AUC which is the main determinant of systemic effect. If rates of secretion or absorption into portal blood are similar between patients, the SAR and HC will determine the AUC. Mehtods are proposed in this grant application to determine the systemic availability ratio and hepatic clearance of PES with great hepatic extraction such as cholylglycine, insulin and ammonia by analysis of the close relationship between hepatic extraction, portal fraction of hepatic blood flow and blood concentrations in vessels entering and leaving the liver. The methodology is simple requiring at the time of transphepatic portal pressure measurement: 1) sampling of portal vein, hepatic vein and arterial blood for cholglycine, ammonia and insulin: 2) 20-second portal infusion of C14 cholylglycine, TC99 microspheres and I131 RISA with hepatic vein sampling, and 3) following IV injection of glucose, ICG and C14 cholylglycine serial sampling from artery and hepatic vein to determine the hepatic extraction ratio of insulin, ICG and C14-cholylglycine and hepatic blood flow. The initial focus of this proposal is on validation of the methodology proposed through: 1) computer simulation, 2) animal experiments and 3) comparison of the SAR of cholylglycine with pharmacologic determination of bioavailability in patients with liver disease. Following validation, it is expected that increased SAR in patients with liver disease will be the prime factor correlating with systemic abnormalities in metabolism of PES including the increased peripheral concentration and the AUC in response to a load. This hypothesis will be tested in 30 patients with liver disease and ten controls.